Motilin is a gastrointestinal linear polypeptide hormone which stimulates the gastric antrum, duodenum, and colon. Although its effects are not completely known, motilin plays a role in increasing gastric motility and stimulating pepsin output and may also be important in regulating the interdigestive myoelectric complex. Human motilin has not yet been purified, but its immunologic properties strongly suggest that it is very similar to porcine motilin. Porcine motilin contains amino acid residues and may be represented by the formula: H-Phe-Val-Pro-Ile-Phe-Thr-Tyr-Gly-Glu-Leu-Gln-Arg-Met-Gln-Glu-Lys-Glu-Arg- Asn-Lys-Gly-Gln-OH (SEQ ID NO:1)
Porcine motilin has a hydrophobic region from positions 1 to 5, a hydrophilic region from positions 11 to 22, and a connecting region from positions 6 to 10. Porcine motilin also has an .alpha.-helical secondary structure from residues 9 to 20 of the primary sequence [Khan et al., Biochemistry 29, 5743-5751 (1990)].
Administration of motilin to healthy human subjects accelerates intestinal transit time and enhances gastric emptying. In vitro, motilin stimulates contractions of human and rabbit duodenal smooth muscle strips and isolated gastrointestinal smooth muscle cells. In addition, motilin and some of its derivatives compete with radiolabelled motilin for binding sites on human and rabbit antral tissue suggesting that stimulation of specific receptors in the gastrointestinal tract is responsible for the physiological effects of the hormone. Infusion of motilin has been reported to stimulate the emptying of solids and liquids in patients with diabetic gastroparesis [Peelers et al., Gastroenterology 100, A480 (1991)]. In addition, motilin has been used to treat patients with paralytic ileus caused by carcinoma of the gastrointestinal tract [Meyer et at., Med. Klin. 86, 515-517 (1991)].
A major problem with motilin is its relatively short half-life (t.sub.1/2) of 4.5 minutes in humans [Christofides et al., Gastroenterology 76, 903-907 (1979)]. This short half-life makes it necessary to administer the hormone by continuous infusion to induce a therapeutic effect.
The N-terminal amino acid sequence and certain residues of the midportion of motilin are essential for contractile activity, [Macielag et at., Peptides 13, 565-569 (1992); Peeters et at., Peptides 13, 1103-1107 (1992); Poitras et at., Biochem. Biophys. Res. Commun. 183, 36-40 (1992)]. Motilin-like polypeptides which have a shorter C-terminus, contain from 3 to 5 basic amino acids bonded from position 12, and have various amino acid substitutions at positions 1 through 11 have been reported to have activity less than, or equal to, that of motilin. None of the motilin-like polypeptides were reported to have increased metabolic stability [Japanese patent no. 2-311,495].
Accordingly, a motilin-like polypeptide having potent gastrointestinal motor stimulating activity and enhanced metabolic stability would be useful for the treatment of decreased basal levels of gastrointestinal motor activity.